Methods and systems for multiforce high throughput screening are disclosed. According to one aspect, the subject matter includes a high throughput screening system that includes a multiforce plate having a plurality of field forming poles where each field forming pole is positioned on the multiforce plate at a location corresponding to a well in a multiwell plate. The system also includes an exciter assembly with excitation poles positioned at locations corresponding to the field forming poles. The excitation poles are utilized for electrically or magnetically coupling to the field forming poles and for delivering at least one of an electric and magnetic field in the vicinity of the field forming poles. The coupled field forming poles apply force via the field(s) to probes located in the wells of the multiforce plate in order to move the probes and test mechanical properties of specimens in the wells.
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34. A method for high-throughput screening of a plurality of specimens to determine electric or magnetic properties of the specimens, the method comprising:
placing the plurality of specimens in wells of a multiwell plate;
providing a multiforce plate with field forming poles located at positions corresponding to wells in the multiforce plate;
bringing an exciter assembly in proximity to the field forming poles for electrically or magnetically coupling to the field forming poles and for producing one of an electric or magnetic effect in the specimen; and
measuring a response of the specimens to determine an electric or magnetic property of the specimens, wherein the exciter assembly and the field forming poles are configured for individual control of force applied to each well of the multiwell plate by providing a flux return path for each well in the multiwell plate that is separate from flux return paths of other wells in the multiwell plate.
22. A high throughput screening system for applying force to a plurality of specimens contained in wells of a multiwell plate, the system comprising:
a multiforce plate having disposed thereon a plurality of field forming poles, each field forming pole being located on the multiforce plate at a location corresponding to a well in a multiwell plate; and
an exciter assembly having excitation poles disposed thereon at locations corresponding to the field forming poles, for electrically or magnetically coupling to the field forming poles, and for producing at least one of an electric and a magnetic effect, wherein the coupled field forming poles apply the effect to specimens located in the wells of the multiwell plate to test electric or magnetic properties of the specimens in the wells, wherein the exciter assembly and the field forming poles are configured for individual control of force applied to each well of the multiwell plate by providing a flux return path for each well in the multiwell plate that is separate from flux return paths of other wells in the multiwell plate.
1. A high throughput screening system for applying force to a plurality of mechanically unattached probes located in specimens contained in wells of a multiwell plate, the system comprising:
a multiforce plate having disposed thereon a plurality of field forming poles, each field forming pole being located on the multiforce plate at a location corresponding to a well in a multiwell plate; and
an exciter assembly having excitation poles disposed thereon at locations corresponding to the field forming poles, for electrically or magnetically coupling to the field forming poles, and for delivering via the field forming poles at least one of an electric and a magnetic field in the vicinity of the field forming poles, wherein the coupled field forming poles apply force via the at least one field to mechanically unattached probes located in the wells of the multiwell plate to move the probes and test mechanical properties of specimens in the wells, wherein the exciter assembly and the field forming poles are configured for individual control of force applied to each well of the multiwell plate by providing a flux return path for each well in the multiwell plate that is separate from flux return paths of other wells in the multiwell plate.
33. A method for providing high throughput screening for applying force to a plurality of mechanically unattached probes located in specimens contained in wells of a multiwell plate, the method comprising:
placing a plurality of mechanically unattached probes in specimens contained in wells of a multiwell plate;
generating an electrical or magnetic field by coupling excitation poles disposed on an exciter assembly with corresponding field forming poles positioned on a multiforce plate, wherein the field forming poles are positioned on the multiforce plate at locations corresponding to the wells in the multiwell plate; and
delivering via the field forming poles at least one of an electric and a magnetic field in the vicinity of the field forming poles, wherein the field forming poles apply force via the at least one field to the plurality of mechanically unattached probes located in the wells to move the probes and test mechanical properties of the specimens in the wells, wherein the exciter assembly and the field forming poles are configured for individual control of force applied to each well of the multiwell plate by providing a flux return path for each well in the multiwell plate that is separate from flux return paths of other wells in the multiwell plate.
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This application claims the benefit of U.S. Provisional Patent Application Ser. No. 60/902,664, filed Feb. 22, 2007, the disclosure of which is incorporated herein by reference in its entirety.
This invention was made with government support under Grant Nos. 5 P41EB002025 and 1 R01 EB000761-01 awarded by the National Institutes of Health. The government has certain rights in the invention.
The subject matter described herein relates to the application of magnetic and/or electrical forces to various specimens and/or to mechanically unattached probes located in the specimens for high throughput screening of at least one of mechanical, chemical, or biological properties of the specimens.
Currently, there is a significant need for force measurements in biological and biomedical sciences. Namely, biological systems respond to forces and stresses such that the responses (both physical and biochemical) can be used to determine the health of a patient. For example, blood clots serve to stem the flow of blood in a wound, and the clotting success relies on the mechanical integrity of protein filaments called fibrin fibers. Similarly, the tissues that line the blood vessels and the lung also respond to stress. These cells are under constant cyclic stress due to the pumping of blood and due to respiration, respectively. In the case of the endothelial cells that line blood vessels, the response of these cell linings determine the release of biochemical agents to retard inflammation. In the case of the epithelial cells that line the lung, the stress response regulates the amount of mucus that coats the lung. With the vast set of biochemical pathways that need to be elucidated and complex mechanisms that need to be explored, the biological sciences have developed high throughput screening where hundreds to millions of experiments can be performed in parallel. However, at this time, there is no equivalent high throughput assay that applies force and measures the biological response to the stress.
Other types of high throughput experiments that can be conducted include magnetic experiments where molecules are separated based on permeability, electrochemical experiments where conductivity of an assay is measured by applying a potential difference and measuring the corresponding current, electrophoresis where molecules in an assay are differentiated based on charge, dielectrophoresis where molecules in an assay are differentiated based on polarizability, frequency dependent electric or magnetic experiments where molecules are differentiated based on frequency response under an applied time varying electric or magnetic field, and combinations of any of these types of experiments.
Accordingly, there exists a need for methods and systems for multiforce high throughput screening methods.
Methods and systems for multiforce high throughput screening are disclosed. According to one aspect, the subject matter disclosed herein includes a multiforce high throughput screening system that includes an exciter assembly having a plurality of excitation poles where each excitation pole is positioned on the exciter assembly at a location corresponding to a well in a multiwell plate. The system also includes a force delivery pole plate with field forming poles positioned at locations corresponding to the excitation poles. The field forming poles are utilized for electrically or magnetically coupling to the excitation poles and for forming at least one of an electric and magnetic field in the vicinity of the specimens. A multiforce plate comprises a conventional multiwell plate and the pole plate. The fields formed by the coupled field forming poles apply force(s) on probes located in the specimen wells of the multiforce plate in order to move the probes and test mechanical properties of specimens in the wells.
The subject matter described herein will now be explained with reference to the accompanying drawings of which:
The subject matter disclosed herein is directed to a multiforce high throughput screening system which can be used to apply electric and/or magnetic fields to mechanically unattached probes located in specimens in a multiwell plate or directly to the specimens themselves. Mechanically unattached probes disposed in the specimen wells may move under the applied electric or magnetic field. Imaging and tracking optics may track the movement of the probes under the applied fields. As a result of the applied fields and the tracked probe movements, mechanical properties of each specimen, such as viscosity can be tested. In applications where electric and/or magnetic fields are applied directly to the specimens, diamagnetic, paramagnetic, dielectrophoretic, electrophoretic, and electrochemical properties of the specimens can be tested. Because the subject matter described herein provides a convenient structure for simultaneously applying electric and/or magnetic fields to plural specimens, multiforce high-throughput screening can be achieved.
As mentioned above, one technique for applying force to a specimen via the system is through magnetic fields. A magnetic probe (e.g., a mechanically unattached bead or rod) may experience a force or torques from magnetic fields and field gradients. Notably, the magnetic force can act on a probe that is placed in a specimen of interest. The specimen may be biological (e.g., a molecule, a cell, a tissue culture, etc.) or of material science interest. The probe may be characterized as one of several magnetic properties (paramagnetic, ferromagnetic, diamagnetic, etc.) and be of arbitrary shape (bead, rod, etc.). The specimen may also be in suspension in a fluid or gel, inside a cell, on top of a cell or cell culture, or anywhere in contact with a biological specimen, such as a tissue specimen or culture. When the magnetic force is applied to the probe, the probe moves in a way that is characteristic of the applied magnetic force and the forces that are imposed by the biological specimen.
There are several approaches to measuring the response of the above-mentioned applied force. For example, the motion of a probe that is influenced by magnetic field may be measured. The response of the probe can then be used as a measure of the specimen's mechanical properties, such as inherent linear and non-linear viscoelastic properties. This particular method of measurement may be useful in biomedical applications such as ascertaining fibrin fiber gel formation and dissolution, as well as determining mucus rheological properties of a specimen. In cases where the probe is attached to a cell, the mechanical properties of the cell may be quantified. Different cell types may exhibit different ranges of stiffness.
A second approach to measuring the response of the applied force may include measuring the motion of the specimen away from the magnetic probe. This measurement approach may be used to identify how stress is conveyed through a molecule, cell, or tissue. The measurement approach may also elucidate pathways in the biochemical response of a biological system.
Yet another approach to measuring the response of the applied force may include monitoring the specimen itself. Namely, the specimen may respond to the applied force by releasing biochemicals, restructuring itself, regulating activity, and the like. These responses can be measured using some other measurement technique, such as using fluorescence microscopy to measure the various degrees of biochemical release.
In one embodiment, multiforce generation subsystem 104 comprises a magnetic drive block, such as exciter assembly 202, which is shown in
Returning to
Referring to
Notably, field forming poles 214 may be positioned in proximity to or may be located inside of wells 212. Each well 212 may contain one or more probes 218. In one embodiment, probes 218 may include mechanically unattached beads or rods that may be magnetized. In a magnetic application, probes can be formed of a paramagnetic or a diamagnetic material. In an electrical application, probes 218 can be charged or chargeable particles. As shown in
In contrast, the activation of force is shown in
In an alternative embodiment, magnetic flux return plate 208 may be replaced by a local return path that serves each coil 206. This may include a cylindrical cap over each coil 206, with flux routed from one end of coil 206 through a field forming pole 214 and back through the outer cylinder to the other end of the coil 206. This implementation may be useful for isolating each well 212 from all of the other wells and by allowing maximum flexibility in the experimental methodology.
Although system 200 was initially designed to be utilized with a standard 96 well plate geometry (e.g., a conventional microtiter plate), system 200 may easily be adapted to accommodate a smaller or larger number of wells.
In one embodiment, control and measurement subsystem 102 may be designed to be computer controlled and is able to generate flux from each of coils 206. The control of the magnetic flux at each coil 206 is achieved by coordinating the currents in the coils so that the coils generate flux either in a limited set of nearby specimen wells 212, or generate fields and forces in every well on multiforce plate 204. Equations to determine which coils to activate for a given configuration of activated specimen wells may be solved by standard linear equations of circuit theory, with known correspondences between magnetic circuit and electrical circuit quantities.
In one embodiment, each field forming pole 214 comprises an elongate member having a teardrop-like shape with a single pole tip. Such an embodiment is illustrated in
Control and measurement subsystem 102 may also include a mechanical properties module 110 that is used to measure the mechanical properties of the specimen depending on the measured movement of the probe. An imaging and tracking optical system 108 may also be employed to perform several kinds of measurements, either simultaneously with the application of force or after the force sequence has been applied. For example, optical system 108 may include a single specimen imaging system with a robotic stage that can systematically position each well 212 over a microscope objective. Alternatively, optical system 108 may include an array based system that is capable of imaging several wells simultaneously. The recorded images may be used to track the probe position, to image strains in the specimen, to detect biochemical activity in the specimen through fluorescence signals, and the like. In one embodiment, optical system 108 may include the placement of a lens in an illumination aperture of exciter assembly 202. Notably, the lens may be embodied as a cylindrical lens that is characterized by a certain gradient index of refraction. The index of refraction that is selected is one that enables the lens to focus a light beam on the specimen as it traverses the narrow length of the illumination aperture. For example, an illumination source, which is placed above the illumination aperture in exciter assembly 202, may be used to project light into the gradient index of refraction lens. The focused light is then directed to the specimen in the specimen well (and a collector and/or microscope objective located on the underside of the specimen well).
In one embodiment, the typical operation of system 200, involves the multiforce plate 204 being loaded with specimens, processed, and then engaged with exciter assembly 202. Together, the combined system may be placed above an inverted microscope objective to measure probe motion (e.g., bead motion) during the application of force via a magnetic field. In cases where the force is to be applied without direct observation, exciter assembly 202 may be energized through some designed sequence in the absence of observation, with the effects of the magnetic forces and fields measured at a later time.
In addition to applying a magnetic field to a plurality of specimen wells, the present subject matter is also capable of selectively powering a single designated well in a multiforce plate according to one embodiment of the subject matter described herein. In
In addition to, or in lieu of, magnetic fields, force may be applied by utilizing electric fields. These electric fields may be constant in time (e.g., direct current (DC) fields) or be applied at various frequencies. The electrical fields can apply forces to objects or molecules that are charged or polarizable. As such, these fields may be applied with the same effects and applications as denoted above for magnetic fields. In one embodiment, system 100 can also apply electric potential, fields, forces and currents to specimens in the multiwell plate. To apply an electric field, electrical contact is made between a given field forming pole and a corresponding excitation pole. In one embodiment, this may be accomplished by making use of the in-place magnetic system (described above) as shown in
The cylindrical openings 808 containing the central coil posts 806 are used to hold the coils that generate flux (e.g., a wire may be wrapped around coil post 806 and contained within cylindrical opening 808). The flux passes through the central post 806 and is coupled into the field forming poles that are mounted to the pole plate on the bottom of a multiforce plate. The flux returns through flux return posts 804 that enter through the multiforce plate through two wells neighboring the specimen well. In one embodiment, exciter assembly 202 may be machined from soft iron for high permeability and saturation, and low hysteresis.
In one embodiment, “pole pattern laminates” are designed to form the bottom of the multiforce plate. Shown in
Multiforce plate 204 may be designed to have field forming poles 214 to be in contact with or proximity to all of the wells 212 simultaneously. In one embodiment, field forming poles 214 may be separate from exciter assembly 202 for convenient changing of the field configuration at the specimen array. In addition, multiforce plate 204 may be either incorporated into the specimen array (i.e., multiwell plate) or be separate. In one embodiment, multiforce plate 204 is incorporated into the multiwell plate so that each well 212 has a number of field forming poles 214 projecting into the specimen well to interact with the specimen.
Many other field forming pole configurations may be envisioned in the specimen well. One possible configuration may include a “pole-pole” geometry which entails two identical poles that may have large forces near each of them, but due to symmetry, have low force in the center. Similarly, a “comb” geometry with multiple sharp tips, each providing force near its region, has been considered. The “comb” configuration may provide larger effective “force-area” product allowing for the application of significant force to more probes within the specimen well.
Similarly, the present subject matter may also be used to form an electrical field gradient in the specimen well to apply forces to electrically polarized particles. In one embodiment, this may be accomplished by inducing a dipole in a molecule or probe by applying a voltage to the field forming pole. This polarizes the molecule (e.g., causes positive particles in the molecule or probe to go to one side and the negative particles to go to the opposite side) in such a way that the gradient of the electrical field pulls the molecule in a certain direction. Notably, different materials are affected by this dielectophoresis effect based on the polarizability of the material.
In one embodiment, the present subject matter may be used to apply an alternating current (AC) field to the specimen well. This frequency dependent embodiment may be achieved by applying an AC voltage to the excitation pole. This action provides a dielectophoresis effect that is unique to each material type. Namely, different materials have different frequency dependencies to dielectric functions. For example, small molecules of a given material may be caused to rotate in response to a rapidly shifting field at a given frequency, whereas large molecules of another material may not respond at this frequency. Thus, the dielectrophoresis effect may be used in this scenario to separate molecules of contrasting size by modifying the frequency of the AC field.
In one embodiment, the present subject matter may be used to conduct electrochemistry tests on specimens. For example, an excitation pole may be provisioned with one or more electrodes that that are used to apply an electric field to a specimen in a specimen well. The electrodes may then be used to monitor current in the specimen. By monitoring the current, changes in the chemistry of the specimen may be detected. Notably, various properties of the specimen may be determined by monitoring the current, such as measuring the conductivity of the specimen.
In block 1104, at least one field is generated. In one embodiment, an electrical and/or magnetic field is created by coupling excitation poles that are disposed on an exciter assembly with corresponding field forming poles positioned on a multiforce plate. The field forming poles may be positioned on the multiforce plate at a location corresponding to the wells in a multiwell plate.
In block 1106, the field forming poles may be used to form fields. In one embodiment, the field forming poles are used to form at least one of an electric or magnetic field in the vicinity of the field forming poles. The field forming poles apply force via the electric or magnetic field and/or their gradients to the probes located in the wells in order to move the probes and test the mechanical properties of the specimens in the wells.
In block 1206, an exciter assembly is brought into the proximity of the field forming poles for electrically or magnetically coupling to the field forming poles and for producing one of an electric or magnetic effect in the specimens. As stated above, the electrical magnetic effect may be an electrophoretic effect, a dielectrophoretic effect, or an electrochemical effect. In block 1208, the effect is measured to determine an electric or magnetic property of the specimen. For example, if the effect is an electrophoretic or dielectrophoretic effect, separation of specimen molecules based on electric charge or polarizability may be measured. If the effect is an electrochemical effect, a voltage may be applied and a corresponding current may be measured to determine conductivity of the specimen. If the effect is a frequency dependent effect, an electric or magnetic field of a particular frequency may be applied and the corresponding frequency responses of the specimens may be measured.
It will be understood that various details, of the presently disclosed subject matter may be changed without departing from the scope of the presently disclosed subject matter. Furthermore, the foregoing description is for the purpose of illustration only, and not for the purpose of limitation.
Vicci, Leandra, Superfine, Richard
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